Fibroblast Growth Factor Receptor (FGFR) belongs to receptor tyrosine kinases. FGFR mainly comprises four members: FGFR1, FGFR2, FGFR3 and FGFR4. FGFRs participate and regulate cell proliferation, migration, apotosis, angiogenesis and many other processes. For their wide functions, FGFRs and other RTKs are strictly regulated under normal conditions. In tumors, such as liver cancer, bladder cancer, lung cancer, breast cancer and prostate cancer, FGFR activation mutation or ligand/receptor over-expression would cause their continuous constitutive activation. It is not only closely related to the occurrence, development and poor prognosis of tumors, but also plays an important role in neovascularization, invasion and metastasis of tumors. Therefore, FGFR was regarded as the important target for antitumor therapy. The development of small molecule inhibitors of FGFR has attracted more and more attention.
The binding of Fibroblast Growth Factor (FGF) to FGFR would cause phosphorylation activation of tyrosine residues or target protein tyrosine residues in receptor intracellular segment. And then activated related transduction pathways through a variety of intracellular signal transducers. At present, it is shown that the downstream cascade signaling pathways induced by FGF include: (1) PKC pathway; (2) Ras/Raf/MEK/Erk pathway; (3) JAK/STAT pathway; (4) PI3K pathway. Interestingly, FGF signaling can activate protein kinases Erk1 and Erk2, and the duration of kinase activity is obviously longer than that of phosphorylated kinase induced by epidermal growth factor (EGF); activation of different pathways can also phosphorylate early transcription factors such as Myc and Fos to promote the transcription of related target genes; at the same time, phosphorylated FGFR can play a role in the directly transfect into the nucleus.
Mutations in FGFR 1 can lead to three genetic diseases: KaLIman syndrome, Pfeiffer syndrome and Osteoglophonic dysplasia. FGFR1 signaling abnormalities were also found in some tumors. It was found that there is highly-expressed FGFR1 in breast cancer, glioma, hepatocellular carcinoma cell. Moreover, abnormal signal transduction mediated by FGFR1 is closely related to fibrotic diseases such as pulmonary fibrosis and cirrhosis of the liver. Studies also found that the mutation of FGFR1 was associated with non-small cell lung cancer and squamous cell lung cancer. Of more than 20 different fibroblast growth factors discovered, FGFR1 can bind to more than 10 different fibroblast growth factors, but preferentially bind to FGF 1 (acidic fibroblast growth factor) and FGF 2 (basic fibroblast growth factor). They have the biological activities of stimulating the growth of fibroblasts, vascular endothelial cells, smooth muscle cells and nerve cells. FGFR1 is their high affinity receptor. When FGF binds to the extracellular segment of FGFR1, the tyrosine kinase active region in the receptor cell segment first phosphorylates itself, then transphosphorylates the receptor target protein, and transmits the ligand signal to the nucleus through protein cascade reaction, which is manifested in promoting injury repair, embryonic development, bone formation, angiogenesis and nerve regeneration.
FGFR2 plays an important role in embryonic development and tissue repair. It also plays a more significant role in bone and angiogenesis. It was also found that it is closely related to tumor angiogenesis, tumor staging, metastasis, prognosis and chemotherapy efficacy. It is over expressed, gene amplificated or missense mutated in many human malignant tumors, such as gastric cancer, lung cancer, breast cancer, ovarian cancer and endometrial cancer. In chronic inflammation, smoking, excessive calorie intake and reduced exercise, the uncontrolled signal of FGFR2 leads to the accumulation of epigenetic modification and gene variation, which causes cancer. FGFR2 is the basis of invasive characteristics of advanced gastric cancer, which is closely related to the pathological type, clinical stage, lymph node and distant metastasis of gastric cancer. FGFR2 has high affinity with many different FGFs. However, the selective splicing of the extracellular region mRNA of FGFR2 makes the C-terminus of the region highly variable, producing two subtypes of high affinity FGFR 2-IIIb or FGFR 2-IIIc with transmembrane structure. FGFR2-IIIb is mainly expressed in epithelial cells, and FGFR2-IIIc is mainly expressed in interstitial cells. FGF7 and FGF10 expressed in stromal cells can specifically activate FGFR2-111b. FGF10 has a higher affinity with FGFR2IIIb and is a specific ligand of FGFR2IIIb. FGF2, FGF4, FGF6, FGF8, FGF9 specifically active FGFR2-IIIc. It was found that FGF7 secreted from gastric stromal cells could promote the growth of gastric cancer cells. The more malignant the cells were, the higher the expression of FGFR2-IIIb was. There was no expression of FGFR in gastric stromal fibrosis cells. Many studies around the molecules of FGFR2 have shown that monoclonal antibodies against FGFR2 have significant inhibitory effects on the high expression or activation of FGFR2 in gastric cancer cells. Combined chemotherapy has synergistic effects on the inhibition of gastric cancer. It shows that FGFR2 is potential good target for the treatment of advanced gastric cancer.
Fibroblast growth factor receptor 3 (FGFR3) not only plays an important role in the development of skeleton, articular cartilage and the maintenance of articular chondrocyte homeostasis, but also plays an important role in osteoarthritis. It has been found that mutation activation of FGFR3 gene can lead to a series of hereditary skeletal development defects, such as fatal dwarfism, achondroplasia, cranial suture premature closure syndrome. Recently, anti-tumour studies have found mutations in FGFR3 gene in multiple myeloma, cervical cancer and bladder cancer, especially in primary and lymph node metastasis bladder cancer. Different mRNA splicing mechanisms in the extracellular domain of FGFR3 produce different FGFR3 receptor homologues, such as: FGFR3a, FGFR3b and FGFR3c. These homologues differ in their selectivity, affinity and tissue expression for ligand binding. For example, FGFR3b is the major form of human epithelial cells and is also the major mutation found in bladder cancer. Of the 23 kinds of FGFs found, FGF9 and FGF18 are relatively specific ligands of FGFR3b. Therefore, targeting-FGFR3 therapies may bring a glimmer of light to bladder cancer patients.
FGFR4 is the major FGF receptor subtype in the liver. Ten of the more than 20 different kinds of fibroblast growth factors (FGF) have been found to bind to FGFR4, of which only FGFR19 binds specifically to FGFR4. Recent studies have shown that changes in FGFR4, such as overexpression, mutation, translocation, and truncation, are associated with the progression of many cancers, including rhabdomyosarcoma, renal cell carcinoma, myeloma, breast cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer and hepatocellular carcinoma.
Therefore, it can be predicted that compounds that inhibit FGFR can be used to treat and prevent FGFR-mediated related diseases, such as cancer, including liver cancer (especially hepatocellular carcinoma), bladder cancer, lung cancer, breast cancer, prostate cancer, rhabdomyosarcoma, renal cell cancer, myeloma, gastric cancer and colon cancer.